Chemical process



g was Feb. s, 1944 CHEMICAL PROCESS Walter C. Meuly, Highland Park, N. .L, assignor to E. I. du Pont de Nemours & Company, Wilj I mington, Del, a corporation of Delaware No Drawing.

Application February 17, 1942. SerlalNo. 431,315

9 Claims. (01. 2604972) This invention relates tothe production of organic poiynuclear compounds and more particularly to the production of provitamins D. more particularly it relates to the production of doubly unsaturated steroids, characterized by Still having two conjugated double bonds in ring 11 of the cyclo-pentano-perhydroephenanthrene nucleus. Still more particularly it relates to novel methods for removing acid groupsirom esters of 7-hydroxy sterols whereby 'l-dehydro sterol compounds areformed.

Certain 7-dehydro sterol compounds arequite commercially important compounds, for examformed may beconverted into 7-dehydro-sterols pie, the -'I-dehydro-sterols are quite valuable provitamins D and can be antirachitically activated to produce vitamin'D; Among the useful strols are 'l-dehydro-stigmasterol, 7-dehydro-cholesteml, and 'I-dehydro-sitosterol. The preparation of these compounds from the corresponding '1- hydroxy sterol esters by various manners-has carboxyllc acids at elevated temperatures under reduced pressures is describedwhereby' 7-dehydrosterol carboxylic acid esters are formed. The

monoesters are saponifled to form "L-dehydrosterols. U. S. P. 2,209,934 describes the production of 7-hydroxysterols from diesters of -'I-hydroxy-sterols with monocarboxylic acids by reacting them with-organicnit en bases 101- lowed by the saponiflcation of the 'i-dehydro sterol ester formed. U. S, P. 2,255,815 describes the treatment of such di-esters with organic salt iorming compounds in the presence-oi oxonium salt forming compounds and also additional materials. These procedures have a number of advantages but also have some disadvantages. For

instance, they require careiul control and super-.

visi0n,,the yields are sometimes low with uneconomical lay-product formation, the assistants are expensive and sometimes relatively unavailable. This invention has for an object, a new method or removing carboxylicacid groups i'rom esters oi A -5,7-hydrcxy steroids with monocarboxylic acids; A further object is to provide such a method using readily available and relatively inexpensive material. A still further object is to provide such a process which involves a simple procedural step. Another object is to provide such. a proess which can be carried out in simple and economical apparatus. Still other, objects will-be apparent from the hereinaiter described invention.

moval by distillation with hydrocarbon solvent.

' It has now been found that 'l-dehydro-steroids can be obtained in an economical manner from A 5,7-hvdroxy steroid esters wherein the 7-hydroxyl group is esterifled with a monocarboxylic acid by heating such esters in the presence of an excess of a hydrocarbon until saidsteroid ester is converted intothe 7-dehydro form. The resulting compounds as a rule crystallize out from the reaction mass-in a state of high purity but they by meeting them with saponifying agents.

It has further been found that the yield oi the desired -7-dehydrosterol can be substantially increased if the amount of hydrocarbon solvent employed is a multiple of the weight .of the '1- hydroxycholesterol ,diacyl ester. Thus I find it advantageous to employ from 5 to parts of hydrocarbon solvent for'each part of ester.

A further aspect of this invention is embodied in the carrying out of the reaction under such conditions of temperature and pressure that the hydrocarbon solvent is at its boiling point and that a portion thereof :is continually being distilled oil and removed from the seat of reaction.

The marked improvement in yield of the de- 'the fact that under the conditions aforementioned, the concentration of liberated monocarboxylic acid in the reaction mass is kept very low at all times, due either to high dilution or to re- While the above explanation may account at least in part for the high yields obtained, neither the high dilution nor the 'distillation oi the hydrocarbon solvent are essential steps of the invention.

According to one practical aspect of the inven-.

tion, 7-dehydro-sterol compounds are obtained in high yields by heating A.5,7-hydroxysterol esters to a temperature between C. and 250 C. while they are uniformly dissolved or dispersed in ,5 to 100 times their weight of hydrocarbons. The

pressure may be atmospheric or sub-atmospheric or super-atmospheric. Alter cooling. the

larger part of the hydrocarbon is removed by distillation, it necessary under diminished pressure, and the desired 7-dehydrosterol ester will hydro-sterol esters can be directly converted to 'l-dehydro-sterols by first extracting the acid formed and then adding a saponifying agent to the hydrocarbon mixture and reacting the same with the 7-dehydro sterol ester to form 'l-dehvdro-sterols. The acid formed can be extracted in like manner, the hydrocarbons distilled off and the sterol purified by crystallization,

In a preferred aspect of the invention, stable, normally liquid hydrocarbons (l, e., hydrocarbons which are liquid at atmospheric pressure at temperatures in excess of 150 C.) are used under conditions such that at least 10 parts of hydrocarbon is at all times present with the A5,7-hydroxy steroid esters. The temperature is preferably\chosen so that the reaction will go to completion in 1 to 10 hours.

The heating can be carried out in various manners by heating the A5,7-hydroxy steroid esters dissolved or dispersed in the hydrocarbon in a vessel which is provided with means for refluxing the vapors or for sealing the same. Agitatlng means can be provided to insure a uniform distribution and prevent local overheating. Jackets forintroducing a heating medium, e. g. water, oil, steam, etc., may be provided or the vessels may be heated by direct fire.

The invention will be further illustrated but is not intended to be limited by the following examples wherein the parts stated are parts by weight unless otherwise specified:

Example I One hundred parts of 7-hydroxycholesterol dibenzoate melting point 173-174" C. and 1000 parts of tetralin (tetrahydronaphthalim areheatedin a vessel provided with a reflux con-- I. The tetralin concentrate will contain crystals of benzoic acid which can be recovered in any desired manner.

Example IV One hundred parts of 7-hydroxycholesterol dibenzoate are heated with 600 parts of naphthalene to' a temperature of 200-220 C. for a period of 3 to 6 hours. After removal of most of the naphthalene in a manner similar to that tiescribed in Example I there are obtained about 50% of pure 7-dehydrocholesteryl benzoate.

Example V In a closed vessel 20 parts of 7-hydroxycholesterol dibenzoate admixed with 400 parts of a petroleum hydrocarbon fraction boiling around 120 C. at ordinary pressure, are heated to about 230 C. for a period of 2 to 6 hours. After cooling, the reaction product is extracted with. an aqueous solution of sodium carbonate in order to remove the benzoic acid formed. To the remaining'hydrocarbcn solution a solution of alcoholic potassium hydroxide is added and the solution is refluxed for one hour to saponify the 7-dehydrocholesterol benzoate which has been formed. The saponification mass, after cooling, is extracted with water and the remaining hydrocarbon soluthat '.the solution contains 2.0%-2.5% benzoic 'methyl alcohol, acetone and the like which promote complete precipitation of the desired product. The benzoic acid formed will stay in solu-- I tion. After filtration there'are obtained 60-70% of 7-dehydrocholesterol benzoate of excellent purity. H

Example II 'One hundred parts of -7-hydroxycholesterol dibenzoate and 200 parts of tetralin are heated in a vessel provided-with a reflux condenser after the manner set forth in Example I. The 7-dehydrocholesterol benzoate is recovered and purified after the manner described in Example I. A yield of 48% of 7-dehydrocholesterol is obtained. The concentration of benzoic acid present at the end of the reaction is about 8%.

Example III w One hundred parts of 7-hydrox'ycholesterol dibenzoate and 200 parts of tetralin are heated in a vessel so that the tetralin distills over at a slow of the tetralin. The small amount of tetralin remaining in the vessel is cooled and the '7-dehydrocholesterol benzoate recovered and purified if desired after the manner set forth in- Example rate requiring about 2 hours to' distill over most tion is subjected to distillation under reduced pressure until about parts of solvent are left. The residue is cooled whereby 7-dehydrocholesterol crystallizes out in a yield of 40-50%.

' In place of the specific hydrocarbon set forth in the above examples there may be substituted a wide variety of hydrocarbons which have the above described characteristics. The useful hydrocarbons are not limited to any one particular type, on the contrary, 'lmple and mixed aliphatic, cycloaliphatic, alicyclic, aromatic and aliphatieally substituted aromatic hydrocarbons which are stable at the reaction temperature, can be used. The hydrocarbons may be substituted by innocuous groups such as chlorine, fiuorine, etc. As examples of suitable additional hydrocarbons mention is made ofcyclohexane, methylcyclohexane, ethylcyclohexane, benzene, toluene, xylene, naphthalene, dihydronaphthalene, decahydro-naphthalene; pinene; heptane, octane, etc., petroleum. ether, benzine, ligroin as well as high boiling mineral oil fractions; halogenated hydrocarbons, e. g., dichloroethane, tetrachloroethane,

chlorobenzene, dichlorobenzenes, chlorotoluene,

benzotrifiuoride, etc.

The quantity of hydrocarbon may be varied over a fairly wide range, e. g., from 1 to 100 parts of hydrocarbon per part of steroid ester. In general, higher yields are obtained by the use of an excess of hydrocarbon. A preferred range is 5 to 25 parts of hydrocarbon per part of steroid ester.

The temperature and time may also be varied over a fairly wide range, e. g., from C. and less to 300 C. and over. A temperature from C. to 260 C. represents a preferred range.

.and crystallizing formed 7-dehydro compound:

' and replenishing the reaction mixture.

It should be understood that the invention is tion of a sterol not limited to the treatment of the specific A 5,7- hydroxy-sterol esters described in the working examples. 'On the contrary, it embraces the treatment of steroids generally wherein a double bond exists in the A 5,6-position regardless of whether additional substituents are also vpresent in other positions in the molecule. Any ester compound having the cyclo-pentano perhydrophenanthrene skeleton may be used wherein the ester group is 'in the 7-position and a double bond 'is in the 5,6-position. Such substances are sometimes termed steroid or sterid com pounds and include those having the nucleus referr d to with or without side chains includin said ains with other functional groups such as oxo. hydroxyl and carboxyl groups and their acetic, cinnamic, formic, propionic, butyric, valeric, etc., acids or their acid anhydrides and' acid halides, e. g., acyl chlorides. Any. of the diesters disclosedin U. S. Patents Nos. 2,209,923 and 2,215,727, for instance, may be used as starting materials in the present processes.

The 7-dehydro steroid esters can be converted into 'l-dehydro. steroids containing hydroxyl steroid characterized by having an esterifi ed hydroxyl group in the 7-position and a double bond in the 5,6-position of a cyclo-pentano-perhydrm' phenanthrene nucleus, which is maintained in.

a liquid hydrocarbon medium until a material amount has been converted into the 7-dehydro form.

2. The process which comprises heating a steroid characterizer by having an esterified hydroxyl group in the '7-position and a double bond in the 5,6-position of a cyclo-pentano-perhydrophenanthrene nucleus, which is dispersed in an excess of a liquid hydrocarbon medium to atemperature from about 150 C. to about 300 C. until .a material amount hasf'been converted intothe 7-dehydro form, removing the acid formed and recovering the 7 -dehydrosteroid.

3. The process which comprises heating a diester of a 7-hydroxy sterol which contains a monocarboxylicacid ester group in the 7- and 3-positions, dispersed in from 5 to parts by weight of a liquid hydrocarbon per part of digroups in the 3-position in various manners.

For example, they may be saponifled by means of acaustic alkali metal hydroxide in alcoholic solution.

Alkaline earth metal hydroxides may be usd in ethyl alcohol solutions if desired.

This invention has a number of advantages in that it enables one to obtain l-dehydro-sterol compounds from esterified 'T-hydroxy steroids in ester to atemperatu're from 150 C. to- 300 C.

until a' material amount has been converted,into

a 7-dehydro-sterol"monoester. 4. The process which comprises heating a diester of a 7-hydroxy sterol which contains a monocarboxylic acid ester group in the '7- and 3-positions, dispersed in .a liquid hydrocarbon medium to a temperature from 150 C. to 300 C. for a pediod oijat least 2 hours and recoverin the 7-dehydro;sterol monoester formed. a

5. The process which comprisesadmixing an.

esterified 7-hydroxy sterol with a stable, liquid hydrocarbon of low viscosity having a boiling point from 150 C.,to 250 C. and heating the re- I suiting mixture to a temperature from about 150 C. to 300 C. for a period of at least 2 hours. 6. The processwhich comprises admixing an esterified 7-hydroxy sterol with an excess of a stable hydrocarbon having a boiling point from a simple manner. A further advantage resides ln'the fact that the hydrocarbons are relatively inexpensive as compared with acid binding agents which have been previously prepared.

Another advantage is that the hydrocarbons are odorless, relatively non-toxic and can be discarded after the use without constituting an economic loss.

The use of the hydrocarbons has an additional advantage that it enables acids to be removed from the esterifled steroids without the necessity of resorting to a high degree of vacuum. In addition, the hydrocarbons form a'practical medium for saponifying ester groups in the 3-.posinucleus whereby sterols are formed.

As many apparently widely different embodiments or thisinvention may be made without departing from the spirit and scope thereof, it

is to be understood that I do not limit myself 4 to especific embodiments herein except-as defin d by the appended claims.

I claim:

1. The process which comprises heating a 150 C. to 250 C. and heating the resulting mixtureyto a temperature from 150 C. to 300 C.

until a material amount of said esterified sterol has been converted into a 7-dehydro-sterol monoester, recovering the acid produced and converting the monester into a 7-dehydro sterol.

7. A process which comprises admixing a mo] of a. diester of a 7-hydroxy-sterol and a monobasic carboxylic acid with from 5 to25 parts .by weight of a stable hydrocarbon per part of diester and heating the resulting mixture to a temperature sufilcient'to split off a carboxylic acid group until a material amountoi said esterifled sterol has been converted into a 'T-dehydro monoester.

8. The process which comprises heating a diester 01 7-hydroxy-cholesterol in the presence of a hydrocarbon which is liquid at room temperature, in order to produce a substantial amount of '7-dehydro-cholesterol ester. 9. The process which comprises heating one part by weight of 7-hydroxy-cholesterol dibenzoate in the presence of from 5 to 25 parts by weight of tetralin to 'a temperature approximating the boiling point of tetralin for a sufflcient period 01' time to produe a substantial amount of v7-clehydro-chloresterol benzoate.

WALTER. c. MEULY. 

